The major histocompatibility complex and multiple sclerosis: a smoking gun?

Abstract

There are many theories on the aetiology of multiple sclerosis but most lack much in the way of direct experimental support. Despite overwhelming evidence that the pathogenesis involves an interplay between genetic and environmental effects, progress in identifying the relevant risk factors has been painfully slow and there is practically no understanding about how these might interact and result in disease. In this issue, Hedstrom et al . (2011) present an integration of a specific genetic and environmental effect. In a case ( n = 843) control ( n = 1209) study carefully designed to reduce potential confounding, they consider established genetic factors (DRB1 and HLA-A) in the context of smoking; and find evidence that the effects on susceptibility attributable to these genetic loci are amplified by this lifestyle exposure. On the basis of this observation, and by analogy with established pathogenic mechanisms in rheumatoid arthritis (Karlson et al ., 2010), they argue that the post-translational modification of lung proteins caused by smoking might lead to multiple sclerosis in genetically susceptible individuals by priming circulating lymphocytes against cross-reacting CNS antigens. This is an intriguing hypothesis, which if confirmed would represent a major step forward in our understanding. Attempting to unravel the pathogenesis of any complex trait through association analysis is a perilous exercise, littered with traps for the unwary. Past experience has shown that researchers using this approach need to pay obsessional attention to detail if they are to avoid adding to the enormous literature confidently describing what turn out to be false positive associations (Ioannidis, 2005). At face value nothing could be simpler than establishing the relevance of an exposure by identifying a difference in its frequency between cases and controls. In this deceptively straightforward paradigm, establishing statistical significance appears to be the most challenging issue; and simultaneously avoiding confounding due to systematic …